Feng Shiyun, Jia Jiabao, Wang Kaizhong, Zhao Hui, Lv Guangchao
Thoracic Surgery, Lung Transplantation Department, First Hospital of Jilin University, 71 Xinmin Street, Chaoyang District, Changchun, 130021, Jilin, China.
Embryology Teaching and Research Office, First Hospital of Jilin University, Changchun, Jilin, China.
J Mol Histol. 2025 Jul 5;56(4):214. doi: 10.1007/s10735-025-10497-1.
Ferroptosis, a regulated cell death mechanism characterized by iron dependency and lipid peroxidation, has been identified as a pivotal driver of tumor evolution and treatment resistance. Our findings reveal a previously unrecognized ubiquitination-driven mechanism in esophageal squamous cell carcinoma (ESCC), whereby F-box protein 10 (FBXO10) modulates ferroptosis susceptibility and oncogenic aggressiveness by orchestrating acyl-CoA synthetase long-chain family member 4 (ACSL4) degradation. Co-immunoprecipitation and immunofluorescence colocalization assays confirmed specific physical interaction between FBXO10 and ACSL4. Mechanistically, FBXO10 silencing stabilized ACSL4 by suppressing ubiquitination degradation, thereby potentiating ferroptosis through amplified lipid peroxidation and Fe⁺ accumulation. Functional studies revealed that FBXO10 ablation suppressed ESCC cell proliferation, migration, and invasion via ACSL4-dependent ferroptosis activation. In vivo validation demonstrated that FBXO10 knockdown attenuated xenograft tumor growth while elevating ferroptotic markers. Crucially, this regulatory axis operates independently of the canonical glutathione peroxidase 4 (GPX4) pathway, as evidenced by preserved GPX4/solute carrier family 7 member 11 (SLC7A11) expression. Our experimental results establish the FBXO10-ACSL4 axis as a core signal axis in ESCC, proposing targeted disruption of this ubiquitination switch to restore ferroptotic susceptibility.
铁死亡是一种以铁依赖性和脂质过氧化为特征的程序性细胞死亡机制，已被确定为肿瘤进展和治疗耐药的关键驱动因素。我们的研究结果揭示了食管鳞状细胞癌（ESCC）中一种以前未被认识的泛素化驱动机制，即F-box蛋白10（FBXO10）通过协调酰基辅酶A合成酶长链家族成员4（ACSL4）的降解来调节铁死亡易感性和致癌侵袭性。免疫共沉淀和免疫荧光共定位分析证实了FBXO10与ACSL4之间存在特异性的物理相互作用。从机制上讲，FBXO10沉默通过抑制泛素化降解来稳定ACSL4，从而通过增强脂质过氧化和Fe⁺积累来增强铁死亡。功能研究表明，FBXO10缺失通过依赖ACSL4的铁死亡激活抑制ESCC细胞的增殖、迁移和侵袭。体内验证表明，FBXO10敲低减弱了异种移植肿瘤的生长，同时提高了铁死亡标志物的水平。至关重要的是，这一调控轴独立于经典的谷胱甘肽过氧化物酶4（GPX4）途径发挥作用，这一点从GPX4/溶质载体家族7成员11（SLC7A11）表达的保留得到证明。我们的实验结果确立了FBXO10-ACSL4轴作为ESCC中的核心信号轴，提出靶向破坏这种泛素化开关以恢复铁死亡易感性。
